This project is a series of translational clinical studies evaluating analgesic strategies in man with potential for enhanced analgesic effects or reduced toxicity in comparison to standard treatments. Subjects undergo oral surgery performed with local anesthesia and demonstrate neuroendocrine responses to pain and stress during the perioperative period as well as acute pain for several days. A study concluded this year demonstrated that the random allocation of local anesthesia either before or after oral surgery performed under general anesthesia resulted in differential effects on the development of pain at 24 and 48 hours. Suppression of intraoperative nociceptive barrage, as confirmed by measurement of plasma beta-endorphin levels, had minimal effects on the development of pain at later time points. Blockade of pain in the first 2-3 hours postoperatively significantly reduced pain at 48 hours, suggesting that postoperative nociceptive barrage in the immediate postoperative period is more important in the development of central hyperalgesia than blockade of the intraoperative barrage. A second study demonstrated rapid analgesic onset following parenteral administration of an NSAID (ketorolac) but with delayed changes in levels of PGE2 at the extraction site. A parallel group receiving a very low dose of ketorolac at the extraction site demonstrated delayed analgesic activity accompanied by decreased PGE2 at the extraction site. These findings are consistent with a central site of analgesic activity initially and a peripheral site of action at later time points associated with suppression of a prototype inflammatory mediator. A retrospective study in greater than 300 subjects failed to demonstrate any influence of gender on the onset of acute pain or its relief following an NDAID analgesic.